The present invention generally relates to a process for producing enediynes and more specifically to a method for synthesizing enediynes containing a hex-3-ene-1,5-diynyl group.
Recently, much attention has focused on systems containing enediyne units as a result of their potential pharmaceutical applications. As used herein, an enediyne refers to a chemical compound containing a carbon double bond (ene) and a pair of carbon triple bonds (diyne). Specifically, enediynes have been incorporated into a number of bioactive agents. The bioactive agents have been studied primarily as antitumor agents in cancer chemotherapy trials.
One example of a possible anti-tumor drug containing an enediyne group is Calicheamicinone. As stated in an article by Haseltine et al. entitled "Total Synthesis of Calicheamicinone: New Arrangements for Actuation of the Reductive Cycloaromatization of Aglycon Congeners" published in The Journal of the American Chemical Society, Volume 113, pages 3850-3866, 1991, which is incorporated herein by reference in its entirety, Calicheamicinone has exhibited remarkably potent cytotoxicity and high cell-killing potential for cancer chemotherapy. In particular, Calicheamicinone and other similar chemical compounds containing enediynes possess DNA-damaging ability. Specifically, these compounds can cause strand scission of DNA via diyl radical attack.
The enediyne contained in Calicheamicinone represents the pharmacophore or active group responsible for its bioactive characteristics. Consequently, one of the components or constituents used in the synthesis of Calicheamicinone is a chemical compound containing the enediyne group and in particular, (Z)-1,6-dilithio-hex-3-ene-1,5-diyne. Unfortunately, this particular dilithio enediyne has been difficult and expensive to produce. In the past, synthesis of dilithio enediynes has been accomplished by first using a procedure derived by Vollhardt et al. as detailed in an article entitled "Stereospecific Synthesis of Cis- and Trans-1,6-Bistrimethylsilyl-Hex-3-Ene-1,5-Diyne" published in Tetrahedron Letters, volume 26, pages 709-712, 1985. Vollhardt et al. more particularly details the synthesis of isomers of 1,6-[bis(trimethylsilyl)]-hex-3-ene-1,5-diyne which is a precursor to the dilithio enediynes in a more protected form. The synthesis of enediynes in Vollhardt et al. includes a palladium-catalized reaction of substituted alkynes and vinyl halides. Specifically, the 1,6-[bis(trimethylsily)]-hex-3-ene-1,5-diynes are made through a catalytic double coupling of trimethylsilylethyne with isomers of dichloroethene. However, this method renders practical scale synthesis prohibitively expensive. Also, environmentally damaging compounds, such as organo chlorine compounds, must be used during synthesis of the enediynes. Consequently, a need exists for an efficient and inexpensive route to producing the needed enediynes.
Besides being used in anti-tumor agents, enediynes have also been found useful in a wide variety of other applications. For instance, enediynes also represent an important class of conjugated .pi. systems with potentially useful optical and electronic properties. Such uses are described by Diederich et al. in ".pi.-Complexes Incorporating Tetraphenyltetraethynylethene" published in The Journal of the Chemical Society, Chemical Communication, pages 205-208, 1994, and incorporated herein by reference in its entirety. However, an efficient reaction scheme for synthesizing enediynes needed in such applications has remained absent from the prior art.
Various enediynes as can be produced by the process of the present invention have also been found useful in the synthesis of polymers and in the synthesis of substituted benzenes. Further uses are disclosed in "Synthesis of Diacetylene Macrocycles Derived from 1,2-Diethynylbenzene Derivatives: Structure and Reactivity of the Strained Cyclic Dimer" by Zhou et al. published in the Journal of Organic Chemistry, pp 1294-1301, 1994, which also is incorporated herein by reference.